Traumatic brain injury (TBI) is a leading cause of death and disability in the human population worldwide, with approximately 2 million reported TBI events occurring in the US annually. Significant cell death occurs within the first days following TBI, resulting in a substantial release of brain proteins and their breakdown products into biofluids such as cerebrospinal fluid (CSF) and circulating blood as facilitated by the compromised brain blood barrier. We recently performed a pilot unbiased investigation to examine if post-TBI patient serum contains autoantibody reactive to one or more brain-specific proteins after TBI. Rather unexpectedly, we found that a significant portion of TBI patients' subacuet sera contains a dominant autoantibody response to a major astrocyte protein GFAP that is proteolytically modified as GFAP breakdown product (GFAP-BDP). We hypothesize that such protease modified GFAP could breakdown the self-tolerance and serve as the dominant autoantigen to trigger autoimmune response following TBI. To examine this hypothesis, we propose to conduct a translational study that combines testing clinical samples and conducting mouse autoimmune studies in vivo as the following: Specific Aim 1 will identify and characterize protease-modified GFAP and accompanied autoantibodies in human CSF and sera post-TBI. Specific Aim 2 will examine systemic immune response and brain pathological consequences in mice following active GFAP-BDP antigen immunization. Lastly, Specific Aim 3 will explore mouse pathological changes as a result of anti-GFAP-BDP autoimmunity in conjunction with experimental TBI. The data generated would provide valuable insight into the pathogenic mechanisms of TBI and likely to support potential development of treatment strategies aimed at reducing the public health burden that follows TBI.